Innate modifiers of T cell behaviour during inflammatory disease
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Date
27/06/2020Author
Minns, Danielle Hayley
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Abstract
Neutrophils are the most abundant leukocyte in mammals and represent one of the first lines
of defence against invading microorganisms. In recent years, it has become clear that
neutrophils are not only responsible for the killing of pathogens, but that they also play an
important role in shaping adaptive immune responses. The aim of this project was to
determine the role of the neutrophil-derived host defence peptide, cathelicidin, in the
generation of Th17 responses during inflammation. Following inoculation with heat-killed
Salmonella typhimurium, cathelicidin knockout mice cannot produce IL-17 and show
increased IFNγ, whereas other cytokines are produced normally. Ex vivo, I show that
cathelicidin is a novel Th17/Tc17 differentiation enhancing factor, which acts directly on both
CD4+ and CD8+ T cells to increase their activation status, protect them from death and
concentration-dependently upregulate IL-17 production. Gene expression analysis revealed
that cathelicidin downregulates the expression of several Th1-related genes and upregulates
the aryl hydrocarbon receptor (AHR), a known regulator of Th17 differentiation. The addition
of an AHR antagonist to our in vitro cultures abolishes the boost to IL-17 production normally
induced by cathelicidin. I provide further evidence that suggests lymph node neutrophils are
the cellular source of cathelicidin, which are responsible for amplifying type-17 responses
during inflammation. These data contribute to our understanding of how lymph node
neutrophils influence developing adaptive immune responses with sophistication and
specificity.